Warren, K. et al. Phase II trial of intravenous lobradimil and carboplatin in childhood brain tumors: a report from the Children's Oncology Group. Cancer Chemother. Pharmacol. 58, 343-347

National Cancer Institute/Neuro-Oncology Branch, Bethesda, MD 20892-8200, USA.
Cancer Chemotherapy and Pharmacology (Impact Factor: 2.77). 09/2006; 58(3):343-7. DOI: 10.1007/s00280-005-0172-7
Source: PubMed


[corrected] Lobradimil is a synthetic bradykinin analog that rapidly and transiently increases the permeability of the blood-brain barrier (BBB). The combination of lobradimil and carboplatin was studied in pediatric patients with primary brain tumors in a phase II trial, the primary endpoints of which were to estimate the response rate and time to disease progression.
Patients were stratified by histology into five cohorts: brainstem glioma, high-grade glioma, low-grade glioma, medullobastoma/primitive neuroectodermal tumor (PNET), and ependymoma. Patients received carboplatin adaptively dosed to achieve a target AUC of 3.5 mg min/ml per day (7 mg.min/ml/cycle) intravenously over 15 min on 2 consecutive days and lobradimil 600 ng/kg ideal body weight/day on 2 consecutive days each 28 day cycle.
Forty-one patients, age 2-19 years, were enrolled; 38 patients, including 1 patient ultimately determined to have atypical neurocytoma, were evaluable for response. No objective responses were observed in the brainstem glioma (n=12) and high-grade glioma (n = 9) cohorts, although two patients with high-grade glioma had prolonged disease stabilization (>6 months). The study was closed for commercial reasons prior to achieving the accrual goals for the ependymoma (n = 8), medulloblastoma/PNET (n = 6) and low-grade glioma (n = 2) cohorts, although responses were observed in 1 patient with PNET and 2 patients with ependymoma.
The combination of lobradimil and carboplatin was inactive in childhood high-grade gliomas and brainstem gliomas.

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    • "Delivery Method Description Most Recent Clinical Trial Chemical-mediated BBB dis- ruption Transient inflammatory response in endothelial lining, investigated w/ LTC4, alkylglycerols, IL-2, RMP-7, bradykinin, & TNF-a/IFN-g Warren et al., 2001 & 2006; Grant et al., 2002 "
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    ABSTRACT: Glioblastoma (GBM) is the most common primary brain tumor and carries a grave prognosis. Despite years of research investigating potentially new therapies for GBM, the median survival rate of individuals with this disease has remained fairly stagnant. Delivery of drugs to the tumor site is hampered by various barriers posed by the GBM pathological process and by the complex physiology of the blood-brain and blood-cerebrospinal fluid barriers. These anatomical and physiological barriers serve as a natural protection for the brain and preserve brain homeostasis, but they also have significantly limited the reach of intraparenchymal treatments in patients with GBM. In this article, the authors review the functional capabilities of the physical and physiological barriers that impede chemotherapy for GBM, with a specific focus on the pathological alterations of the blood-brain barrier (BBB) in this disease. They also provide an overview of current and future methods for circumventing these barriers in therapeutic interventions. Although ongoing research has yielded some potential options for future GBM therapies, delivery of chemotherapy medications across the BBB remains elusive and has limited the efficacy of these medications.
    Neurosurgical FOCUS 03/2015; 38(3):E10. DOI:10.3171/2015.1.FOCUS14767 · 2.11 Impact Factor
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    • "Delivery Method Description Most Recent Clinical Trial Chemical-mediated BBB dis- ruption Transient inflammatory response in endothelial lining, investigated w/ LTC4, alkylglycerols, IL-2, RMP-7, bradykinin, & TNF-a/IFN-g Warren et al., 2001 & 2006; Grant et al., 2002 "
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    ABSTRACT: Object: Fluorescein, a dye that is widely used as a fluorescent tracer, accumulates in cerebral areas where the blood-brain barrier is damaged. This quality makes it an ideal dye for the intraoperative visualization of high-grade gliomas (HGGs). The authors report their experience with a new fluorescein-guided technique for the resection of HGGs using a dedicated filter on the surgical microscope. Methods: The authors initiated a prospective Phase II trial (FLUOGLIO) in September 2011 with the objective of evaluating the safety of fluorescein-guided surgery for HGGs and obtaining preliminary evidence regarding its efficacy for this purpose. To be eligible for participation in the study, a patient had to have suspected HGG amenable to complete resection of the contrast-enhancing area. The present report is based on the analysis of the short- and long-term results in 20 consecutive patients with HGGs (age range 45-74 years), enrolled in the study since September 2011. In all cases fluorescein (5-10 mg/kg) was injected intravenously after intubation. Tumor resection was performed with microsurgical technique and fluorescence visualization by means of BLUE 400 or YELLOW 560 filters on a Pentero microscope. Results: The median preoperative tumor volume was 30.3 cm(3) (range 2.4-87.8 cm(3)). There were no adverse reactions related to fluorescein administration. Complete removal of contrast-enhanced tumor was achieved in 80% of the patients. The median duration of follow-up was 10 months. The 6-months progression-free survival rate was 71.4% and the median survival was 11 months. Conclusions: Analysis of these 20 cases suggested that fluorescein-guided technique with a dedicated filter on the surgical microscope is safe and allows a high rate of complete resection of contrast-enhanced tumor as determined on early postoperative MRI. Clinical trial registration no.: 2011-002527-18 (EudraCT).
    Neurosurgical FOCUS 02/2014; 36(2):E5. DOI:10.3171/2013.11.FOCUS13487 · 2.11 Impact Factor
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    • "Several strategies have been employed to overcome the BBB and improve drug delivery to the tumor site. These include the use of high dose chemotherapy with stem cell rescue (Finlay and Zacharoulis, 2005), biologic or osmotic BBB disruption (Hall et al., 2006; Warren et al., 2006), and p-glycoprotein inhibition (Greenberg et al., 2005). Most recently, convection-enhanced delivery has been used to deliver agents directly into the tumor of patients with DIPG (Lonser et al., 2007). "
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    ABSTRACT: Diffuse intrinsic pontine gliomas (DIPGs) are amongst the most challenging tumors to treat. Surgery is not an option, the effects of radiation therapy are temporary, and no chemotherapeutic agent has demonstrated significant efficacy. Numerous clinical trials of new agents and novel therapeutic approaches have been performed over the course of several decades in efforts to improve the outcome of children with DIPG, yet without success. The diagnosis of DIPG is based on radiographic findings in the setting of a typical clinical presentation, and tissue is not routinely obtained as the standard of care. The paradigm for treating children with these tumors has been based on that for supratentorial high-grade gliomas in adults as the biology of these lesions were presumed to be similar. However, recent pivotal studies demonstrate that DIPGs appear to be their own entity. Simply identifying this fact releases a number of constraints and opens opportunities for biologic investigation of these lesions, setting the stage to move forward in identifying DIPG-specific treatments. This review will summarize the current state of knowledge of DIPG, discuss obstacles to therapy, and summarize results of recent biologic studies.
    Frontiers in Oncology 12/2012; 2:205. DOI:10.3389/fonc.2012.00205
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